8th Conference on Retroviruses and Opportunistic Infection

One of the most important conferences of the year, the 8th Conference on Retroviruses and Opportunistic Infection (CROI) was held in Chicago during the first part of February. Attendees arrived with another year of hope for new treatments, advances on vaccines and a better understanding of HIV-infection. The opening ceremony offered a vivid description of the disparities that currently exist between industrialized countries such as the United States and undeveloped continents such as Africa where more than 17 million deaths have occurred due to HIV-infection. At least 1 in 5 adults are living with HIV infection and more than 12 million children have been orphaned by a disease that continues to remain unnamed because of fear and discrimination. Africa is a continent that is torn by a lack of medical care, medicines that remain financially out of reach, and where the average family lives on less than $250 a year. A continent that is virtually unsupported by the industrialized world. Africa is a continent that will have more than half of its population infected with HIV or dead by the year 2010. This opening presentation set a somber tone for the remainder of the conference.

PEP

Several posters demonstrated data collection for a post-exposure high-risk sexual prophylaxis (PEP) and the possible influence that PEP may have on reducing the HIV infection rates. Slowly, researchers have begun acknowledging that there is a need to offer high-risk exposure prophylaxis to more than just health care workers and that perhaps, the sexual partners of individuals known to be HIV infected should be more extensively studied. Both studies found that behavior did change if those individuals involved in the study knew that they had access to PEP. Questions that remain are whether access to PEP may lead to an increased risk of antiretroviral therapy (ART) resistant strains of HIV and whether PEP is truly protective against HIV transmission. Another study showed that viral load continues to be an independent risk factor for HIV transmission, which means the higher the plasma viral load the more likely that HIV may be transmitted to an uninfected sexual partner. One study looking at the prevalence (how common) of HIV-1 resistance showed that there has been an increase in the number of acute primary HIV infected individuals presenting with resistance to currently available ART. What this will mean in the future remains unclear.

Resistance testing is not currently considered the standard of care for an acute primary infection in most health care settings due to the lack of funding to provide resistance testing. However, routine resistance testing for those individuals who are thought to be experiencing acute seroconversion may need to be considered.

Recommendations

Revised recommendations from the Department of Health and Human Services (DHHS) guidelines committee have suggested deferring antiretroviral therapy until the CD4 T-cell count declines to less than 350 cells, unless vRNA is greater than 50,000 copies/mL. Data was also presented indicating there may be a diminished effectiveness of ART among patients starting HAART with a CD4+ T-cell count less than 200/mm3. (The lower the CD4+ T-cell count, the more difficult it is for some patients to respond to medications, showing increases in lymphocytes and suppression of the viral replication.) The long-term survival after starting HAART study (HAART is defined as a potent combination of antiretroviral medications such as two NRTIs and a PI or NNRTI) showed that the effectiveness of HAART is not dependent on someone's age, gender, or whether they have an AIDS defining diagnosis, and regardless of plasma HIV RNA levels. But again, effectiveness is dependent on the CD4+ T-cell count. Several posters showed that the combination of an NNRTI (such as EFV or NVP) plus two NRTIs might provide long-term virologic success. In other words, if the medications are taken they generally work.

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Reservoirs

Several posters presented data on the presence of persistent HIV replication in "sanctuary" sites such as the genital tract, spinal fluid or lymph nodes and that this may contribute to the development of viral resistance. The male and female genital tract appears to represent a separate compartment, where virus has been isolated either during primary HIV-1 seroconversion or in a patient who is on stable ART. This demonstrates a difference in genital viral load compared to viral load from plasma (blood). Currently, we cannot measure drug penetration into the genital tract, but we can measure viral load. The GI tract (stomach and intestines) was identified as a new potential reservoir. Low levels of detectable HIV RNA were present in the gastric mucosa. The rectal mucosa has also shown a low level of viral replication along with T-cell depletion in chronic HIV-infection.

New Drug Therapies

Promising agents currently in development are still several years away from becoming available to the general patient population. Several posters presented information on the use of ritonavir (Norvir) as an enhancer for other PIs such as indinavir (Crixivan), amprenavir (Agenerase) and saquinavir (Fortavase). This also includes Kaletra where Norvir enhances the effects of loprinavir leading to a very potent PI. Newer agents that are in development appear to offer new mechanisms of action. These include new classes of therapies such as entry inhibitors, fusion inhibitors, chemokine receptor inhibitors, HIV integrase, REV inhibitors and CD4 receptor inhibitors. Adherence continues to play an important role in virologic rebound and the development of viral resistance. Virologic failure due to poor adherence may be as high as 50%. One solution is direct observational therapy (DOT), which has proven to be very effective in improving adherence to TB medications. The use of DOT has been shown to be very useful in administering ART therapy demonstrated by a higher percentage of the participants being less than 50 copies/mL in the DOT arm when compared to the self-administered arm. The success rate in the DOT study may be due to nothing more than simplifying drug regimens with once a day dosing of medications. Whether you look at medical event monitoring systems (MEMS) caps, MediMom or pill counts, adherence to therapy is important and should be discussed at each clinic appointment. Therapeutic drug monitoring (TDM) may prove to be useful in the future. TDM assists clinicians with assessing drug concentration thereby increasing drug dosing to improve drug concentrations or decreasing drug concentration to prevent the development of drug induced toxicities. TDM may prove to be very important to women in determining whether women are currently being overdosed on medications, which can lead to an increase in medication toxicity and side effects.

Scheduled Treatment Interruption (STI)

Data continues to be limited on STIs and should not be attempted by clinicians or patients outside of a controlled clinical trial; STI appears to be successful in some people who receive treatment during primary infection. In several small samples, individuals on STI had significantly lower viral loads and higher CD4+ T-cell counts, lower values of immune markers and higher specific T-cell and CTL responses against HIV-1 than a control group of patients who were ART naive. More data needs to be collected demonstrating that STI does not lead to virologic failure. Patients who have failed ART and are beginning a salvage regimen may benefit from an STI before starting their new therapy. Off ART for 12 weeks may lead to the virus reverting back to wild type, which may improve virologic response to a new regimen. Still, there really is not enough data to support the long-term benefits of STI in salvage therapies.

Hepatitis

Hepatitis B (HBV) and hepatitis C (HCV) continue to increase the morbidity and mortality of people who are co-infected with HIV disease. Several studies reported that we may be missing HBV (26%) and HCV (12%) in late stage infection where medical therapies continue to be disappointing. Several posters presented positive results in those patients who received liver transplants, however this is not an option for everyone. The progress in furthering our understanding of HBV and HCV continues to be small with a possibility of a vaccine many years away.

Metabolic Complications

Metabolic complications of ART continue to be problematic with a definitive answer to the cause of lipodystrophy (LDS) remaining outside of our reach. Do protease inhibitors increase the risk of cardiovascular events was a topic of both concern and discussion. A large ACTG study is currently enrolling trials of HIV-positives on a PI or NNRTI and HIV negatives as a control group. The study uses ultrasound (UTZ) to measure the thickness of the carotid artery looking for difference in the thickness. An increase in carotid artery thickness may suggest an increased risk of cardiovascular events. Mitochondrial toxicity and osteopenia (thinning of the bones) were also reported. Mitochondrial toxicity and osteopenia may be due to antiretroviral medication, but it still remains unclear (we still are not sure what the cause is). Ethnicity may be protective in the development of LDS. Participants in a small study found that being of Korean decent may be protective. Switching to efavirenz from a PI based therapy does not seem to improve insulin resistance after one year in HIV patients with LDS. However, nevirapine containing ART results show an anti-athrogenic (doesn't appear to affect the lipids) plasma lipid profile.

Gender Differences

Very little data about women and HIV infection was presented at the conference. There were over 31 abstracts and posters listed under women, however only 5 dealt with women specifically. The remainder of the "women's" studies were either perinatal or involved the genital tract. This reinforces the need to encourage researchers to focus more on the differences in absorption, distribution and tolerability of antiretroviral therapy in women. It cannot be assumed that women and men respond to or tolerate medications in the same way. Testosterone increases weight and lean body mass in HIV infected women with weight loss. Hoarseness, hairsutism (increased production of secondary hair growth), and clitoral enlargement, while rare, occurred primarily in the testosterone group. One of the first studies developed by Agouron Pharmaceuticals entitled "Women First" presented their final 49-week data showing that the combination of Viracept/Invirase/Zerit/Epivir is effective, safe and well tolerated in women dosed at twice daily.

At the conclusion of the 8th CROI, several questions remained unanswered. Are we seeing a new trend in the transmission of HIV/AIDS resistance? Can these trends be due to poor adherence, under suppressed treatment options and increases in risky behavior? What impact will these trends have on the current epidemic in developed countries? How much longer until we have a vaccine against HIV that works?

In closing, it is important to recognize the global nature of the HIV/AIDS epidemic, including the need for the development of drugs and vaccines that are accessible to all people. Working together toward an improvement in clinical management and a reduction in risky behavior needs to be incorporated into the management of all HIV infected patients.

Prevent HIV infection; it is still the only cure. We need more research addressing the needs of women! We all need to become involved in the fight and make a difference!

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